Special Edition 2021

ADVERSE EFFECTS

Apixaban, edoxaban, rivaroxaban: situations with a high risk of bleeding or thrombosis

ABSTRACT

available to quantify the anticoagulant effect of xabans.This effect is achieved within 2 to 4 hours. Their plasma half-life is about 12 hours (1,3). This relatively short duration of effect is an advantage in the event of overdose or bleeding, but a disad- vantage when patients are underdosed or miss a dose. As of 2020, which situations are associated in practice with a particularly high risk of bleeding or thrombosis during treatment with apixaban , edo­ xaban or rivaroxaban ? This review is mainly based on data provided in documentation published by drug regulatory agen- cies and on the results of clinical trials and pharma­ coepidemiological studies identified through our literature search (see “Literature search and meth- odology” p. 241). Thousands of cases of sometimes fatal bleeding or thrombosis linked to xabans have been reported since the late 2000s in France and other countries. The French Health Products Agency (ANSM) con- ducted a national pharmacovigilance survey on rivaroxaban between 2009 and 2015. 2989 cases of serious adverse effects were recorded (5,6). 1911 cases (64%) were bleeding events, 1131 of which were serious, mainly involving the digestive tract or the central nervous system. Among the 548 cases of thrombosis, 360 cases were serious, and included venous thromboembolism, pulmonary embolism, and ischaemic stroke. 250 of the 324 deaths were linked to bleeding. The ANSM conducted a national pharmacovigi- lance survey on apixaban between 2012 and 2017. Among the 1296 cases of serious adverse effects recorded, 60% were bleeding events, mainly involv- ing the central nervous system or digestive tract. 115 of the 149 deaths were linked to bleeding (5-10). Bleeding has also accounted for a large proportion of the adverse effects reported with xabans in other countries (the Netherlands, Norway, Australia, Canada, the United States, and Japan) (11-15). Reports: mainly bleeding

● Apixaban , edoxaban and rivaroxaban are direct oral anticoagulants that inhibit factor Xa. No rou- tine laboratory tests are available to quantify their anticoagulant effect as of mid-2020, whereas the effect of the standard oral anticoagulant, warfarin , can be easily monitored using the INR. ● Data from clinical trials, cohort studies and pharmacovigilance can be used to identify situ­ ations that increase the risk of bleeding or throm- bosis, some of which involve medication errors. ● The main situations and errors known to increase the risk of bleeding with xabans are: advanced age; renal or hepatic impairment; low bodyweight (body mass index (BMI) less than 18.5 kg/m²); certain conditions that increase the likelihood of bleeding; and drug interactions that increase blood xaban levels or involve drugs with additive bleeding effects. ● The main situations and errors known to increase the risk of thrombosis with xabans are: missed or delayed doses; drug interactions that lower blood xaban levels or involve drugs with antagonistic effects; a period of under-anticoagulation when switching to a vitamin K antagonist; and, in the case of edoxaban , creatinine clearance greater than 95 ml/min. ● In practice, as of mid-2020, when using xabans, it is essential to take into account the situations that increase the risk of bleeding or thrombosis, and to monitor the patient for any change in these risks, such as new comorbidities, new drugs, or discontinued drugs. Rev Prescrire 2020; 40 (441): 506-509 A pixaban , edoxaban and rivaroxaban (also called xabans) are direct oral anticoagulants that inhibit factor Xa, hence the stem -xaban in their international nonproprietary names (INNs). They are authorised for the prevention or treatment of thrombosis in various medical and surgical set- tings. As with all anticoagulants, their main adverse effect is the risk of potentially severe or even fatal bleeding through over-anticoagulation. Conversely, under-anticoagulation carries the risk of throm­ bosis (1-4). The management of xaban therapy is challenging. As of mid-2020, no routine laboratory tests are

Full review (4 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire July 2020 Volume 40 N° 441 • Pages 506-509

Prescrire Int • October 2020

P rescrire I nternational S pecial E dition 2021 • P age 11